ProjectTitle: ModificationofTroponinTtoImproveCardiacFunctioninHeartFailure ProjectSummary Cardiacmusclecontractionisregulatedviathetroponincomplexinsarcomericthinfilaments.Troponin consists of three protein subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). A restrictive cleavage that selectively removes the N-terminal variable region of cardiac TnT (cTnT) naturally occurs as an adaptation to myocardial energetic crisis such as ischemia or pressure overload. The N-terminal truncated cTnT (cTnT-ND) remains in the cardiac myofilaments with altered functionality to physiologically tune down left ventricular systolic velocity, which elongates the phase of rapid ejection, thereby increasing stroke volume and improving the energetic efficiency of the heart. The proposed research will characterize the mechanism by which cTnT-ND alters the kinetics of myofilament activity to allow the heart to physiologically compensate for energetic crisis, and will ultimately lay groundwork for the development of newtargetedtreatmentsforheartfailure.ThreeSpecificAimsareproposed: AimIistocharacterizehowthedeletionoftheN-terminalvariableregionofcTnTrestoresarepressed TnI-like C-terminal conformation to result in a conditional inhibition of myofilament ATPase and contractile kinetics. Aim II is to assess the effectiveness of cTnT-ND on compensating for cardiac dysfunction and improvingcardiacefficiencyinheartfailuremousemodelswithinvivoandexvivofunctionalstudies. Aim III is to assess the long-term effects of cTnT-ND on cardiac function, reserve and remodeling in normalandfailingmouseheartsfortranslationtonewtreatmentsforheartfailure. Significance:Heartfailureisamajorchallengeinthemanagementofcardiovasculardiseases.While b?-adrenergic blockade has proven to be clinically effective in treating chronic congestive heart failure, the long-term benefit of decreasing contractile kinetics remains incompletely understood. The restrictive deletion of the N-terminal segment of cTnT naturally occurs during myocardial ischemia and pressure overloadasaposttranslationalregulationtoselectivelytunedowncontractilevelocityofcardiacmuscleand elongate the rapid ejection phase to increase stroke volume and cardiac efficiency. This mechanism provides a novel and specifically targeted approach to sustain baseline cardiac function during energetic crisis and heart failure. Using multi-level and integrative approaches, our study will lay the groundwork for translatingthismolecularmechanismintoanewclinicaltreatmentforheartfailure.